Topiramate is a white crystalline powder with a bitter taste. Topiramate USP is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution has a pH of 6.3. Topiramate has the molecular formula CHNOS and a molecular weight of 339.37. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

The studies described in the following sections were conducted using topiramate tablets.

The effectiveness of topiramate as initial monotherapy in
adults and children 10 years of age and older with partial onset or primary
generalized seizures was established in a multicenter, randomized, double-blind,
parallel-group trial.

The trial was conducted in 487
patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented
seizures during the 3-month retrospective baseline phase who then entered
the study and received topiramate 25 mg/day for 7 days in an open-label fashion.
Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis
of epilepsy for greater than 24 months. Any AED therapy used for temporary
or emergency purposes was discontinued prior to randomization. In the double-blind
phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day.
If the target dose could not be achieved, patients were maintained on the
maximum tolerated dose. Fifty eight percent of patients achieved the maximal
dose of 400 mg/day for ≥ 2 weeks, and patients who did not tolerate
150 mg/day were discontinued. The primary efficacy assessment was a between
group comparison of time to first seizure during the double-blind phase. Comparison
of the Kaplan-Meier survival curves of time to first seizure favored the topiramate
400 mg/day group over the topiramate 50 mg/day group (p=0.0002, log rank test;
Figure 1
). The
treatment effects with respect to time to first seizure were consistent across
various patient subgroups defined by age, sex, geographic region, baseline
body weight, baseline seizure type, time since diagnosis, and baseline AED
use.

The effectiveness of topiramate as an adjunctive treatment
for adults with partial onset seizures was established in six multicenter,
randomized, double-blind, placebo-controlled trials, two comparing several
dosages of topiramate and placebo and four comparing a single dosage with
placebo, in patients with a history of partial onset seizures, with or without
secondarily generalized seizures.

Patients in these
studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition
to topiramate tablets or placebo. In each study, patients were
stabilized on optimum dosages of their concomitant AEDs during baseline phase
lasting between 4 and 12 weeks. Patients who experienced a prespecified minimum
number of partial onset seizures, with or without secondary generalization,
during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week
baseline, or 3 for 4-week baseline) were randomly assigned to placebo or a
specified dose of topiramate tablets in addition to their other
AEDs.

Following randomization, patients began the double-blind
phase of treatment. In five of the six studies, patients received active drug
beginning at 100 mg per day; the dose was then increased by 100 mg
or 200 mg/day increments weekly or every other week until the assigned
dose was reached, unless intolerance prevented increases. In the sixth study
(119), the 25 or 50 mg/day initial doses of topiramate were followed by respective
weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was
reached. After titration, patients entered a 4, 8, or 12-week stabilization
period. The numbers of patients randomized to each dose, and the actual mean
and median doses in the stabilization period are shown in
Table 1
.

The effectiveness of topiramate as an adjunctive treatment
for pediatric patients ages 2 to 16 years with partial onset seizures was established
in a multicenter, randomized, double-blind, placebo-controlled trial, comparing
topiramate and placebo in patients with a history of partial onset seizures,
with or without secondarily generalized seizures.

Patients
in this study were permitted a maximum of two antiepileptic drugs (AEDs) in
addition to topiramate tablets or placebo. In this study, patients
were stabilized on optimum dosages of their concomitant AEDs during an 8-week
baseline phase. Patients who experienced at least six partial onset seizures,
with or without secondarily generalized seizures, during the baseline phase
were randomly assigned to placebo or topiramate tablets in addition
to their other AEDs.

Following randomization, patients
began the double-blind phase of treatment. Patients received active drug beginning
at 25 or 50 mg per day; the dose was then increased by 25 mg to
150 mg/day increments every other week until the assigned dosage of 125,
175, 225, or 400 mg/day based on patients' weight to approximate a dosage
of 6 mg/kg per day was reached, unless intolerance prevented increases.
After titration, patients entered an 8-week stabilization period.

The effectiveness of topiramate as an adjunctive treatment
for primary generalized tonic-clonic seizures in patients 2 years old and
older was established in a multicenter, randomized, double-blind, placebo-controlled
trial, comparing a single dosage of topiramate and placebo.

Patients
in this study were permitted a maximum of two antiepileptic drugs (AEDs) in
addition to topiramate or placebo. Patients were stabilized
on optimum dosages of their concomitant AEDs during an 8-week baseline phase.
Patients who experienced at least three primary generalized tonic-clonic seizures
during the baseline phase were randomly assigned to placebo or topiramate in
addition to their other AEDs.

Following randomization,
patients began the double-blind phase of treatment. Patients received active
drug beginning at 50 mg per day for four weeks; the dose was then increased
by 50 mg to 150 mg/day increments every other week until the assigned
dose of 175, 225, or 400 mg/day based on patients' body weight to approximate
a dosage of 6 mg/kg per day was reached, unless intolerance prevented
increases. After titration, patients entered a 12-week stabilization period.

The effectiveness of topiramate as an adjunctive treatment
for seizures associated with Lennox-Gastaut syndrome was established in a
multicenter, randomized, double-blind, placebo-controlled trial comparing
a single dosage of topiramate with placebo in patients 2 years of age and
older.

Patients in this study were permitted a maximum
of two antiepileptic drugs (AEDs) in addition to topiramate or
placebo. Patients who were experiencing at least 60 seizures per month
before study entry were stabilized on optimum dosages of their concomitant
AEDs during a 4-week baseline phase. Following baseline, patients were randomly
assigned to placebo or topiramate in addition to their other
AEDs. Active drug was titrated beginning at 1 mg/kg per day for a week; the
dose was then increased to 3 mg/kg per day for one week then to 6 mg/kg per
day. After titration, patients entered an 8-week stabilization period. The
primary measures of effectiveness were the percent reduction in drop attacks
and a parental global rating of seizure severity.

In all add-on trials, the reduction in seizure rate from
baseline during the entire double-blind phase was measured. The median percent
reductions in seizure rates and the responder rates (fraction of patients
with at least a 50% reduction) by treatment group for each study are shown
below in
Table 2
. As described above, a global improvement in seizure severity was
also assessed in the Lennox-Gastaut trial.

Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race,
age, baseline seizure rate, or concomitant AED.

Table 1: Topiramate Dose Summary During the Stabilization
Periods of Each of Six Double-Blind, Placebo-Controlled, Add-On Trials in
Adults with Partial Onset Seizuresb

Target Topiramate
Dosage (mg/day)

Protocol

Stabilization Dose

Placeboa

200

400

600

800

1,000

a Placebo
dosages are given as the number of tablets. Placebo target dosages were as
follows: Protocol Y1, 4 tablets/day; Protocols YD and Y2, 6 tablets/day;
Protocol Y3 and 119, 8 tablets/day; Protocol YE, 10 tablets/day.

b Dose-response
studies were not conducted for other indications or pediatric partial onset
seizures.

j Percent
of subjects who were minimally, much, or very much improved from baseline

*
For Protocols YP and YTC, protocol-specified target dosages (<9.3 mg/kg/day)
were assigned based on subject's weight to approximate a dosage of 6 mg/kg
per day; these dosages corresponded to mg/day dosages of 125, 175, 225, and
400 mg/day.

Partial Onset Seizures

Studies in Adults

YD

N

45

45

45

46

--

--

--

Median % Reduction

11.6

27.2a

47.5b

44.7c

--

--

--

% Responders

18

24

44d

46d

--

--

--

YE

N

47

--

--

48

48

47

--

Median % Reduction

1.7

--

--

40.8c

41.0c

36.0c

--

% Responders

9

--

--

40c

41c

36d

--

Y1

N

24

--

23

--

--

--

--

Median % Reduction

1.1

--

40.7e

--

--

--

--

% Responders

8

--

35d

--

--

--

--

Y2

N

30

--

--

30

--

--

--

Median % Reduction

-12.2

--

--

46.4f

--

--

--

% Responders

10

--

--

47c

--

--

--

Y3

N

28

--

--

--

28

--

--

Median % Reduction

-20.6

--

--

--

24.3c

--

--

% Responders

0

--

--

--

43c

--

--

119 N

91

168

--

--

--

--

--

Median % Reduction

20.0

44.2c

--

--

--

--

--

% Responders

24

45c

--

--

--

--

--

Studies in Pediatric Patients

YP

N

45

--

--

--

--

--

41

Median % Reduction

10.5

--

--

--

--

--

33.1d

% Responders

20

--

--

--

--

--

39

Primary Generalized Tonic-Clonich

YTC

N

40

--

--

--

--

--

39

Median % Reduction

9.0

--

--

--

--

--

56.7d

% Responders

20

--

--

--

--

--

56c

Lennox-Gastaut Syndromei

YL

N

49

--

--

--

--

--

46

Median % Reduction

-5.1

--

--

--

--

--

14.8d

% Responders

14

--

--

--

--

--

28g

Improvement in Seizure Severityj

28

--

--

--

--

--

52d

Topiramate tablets are indicated as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures.

Effectiveness was demonstrated in a controlled
trial in patients with epilepsy who had no more than 2 seizures in the 3 months
prior to enrollment. Safety and effectiveness in patients who were converted
to monotherapy from a previous regimen of other anticonvulsant drugs have
not been established in controlled trials.

Topiramate tablets are indicated as adjunctive therapy for adults
and pediatric patients ages 2 to 16 years with partial onset seizures,
or primary generalized tonic-clonic seizures, and in patients 2 years of age
and older with seizures associated with Lennox-Gastaut syndrome.

Topiramate tablets are contraindicated in patients with
a history of hypersensitivity to any component of this product.

A syndrome consisting of acute myopia associated with secondary
angle closure glaucoma has been reported in patients receiving topiramate.
Symptoms include acute onset of decreased visual acuity and/or ocular pain.
Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular
hyperemia (redness) and increased intraocular pressure. Mydriasis may or may
not be present. This syndrome may be associated with supraciliary effusion
resulting in anterior displacement of the lens and iris, with secondary angle
closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years
of age, secondary angle closure glaucoma associated with topiramate has been
reported in pediatric patients as well as adults. The primary treatment to
reverse symptoms is discontinuation of topiramate as rapidly
as possible, according to the judgment of the treating physician. Other measures,
in conjunction with discontinuation of topiramate, may be helpful.

Elevated
intraocular pressure of any etiology, if left untreated, can lead to serious
sequelae including permanent vision loss.

Oligohidrosis (decreased sweating), infrequently resulting
in hospitalization, has been reported in association with topiramate use.
Decreased sweating and an elevation in body temperature above normal characterized
these cases. Some of the cases were reported after exposure to elevated environmental
temperatures.

The majority of the reports have been
in children. Patients, especially pediatric patients, treated with topiramate should be monitored closely for evidence of decreased sweating and increased body
temperature, especially in hot weather. Caution should be used when topiramate is
prescribed with other drugs that predispose patients to heat-related disorders;
these drugs include, but are not limited to, other carbonic anhydrase inhibitors
and drugs with anticholinergic activity.

Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 3 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing topiramate or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Table 3 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e.,
decreased serum bicarbonate below the normal reference range in the absence
of chronic respiratory alkalosis) is associated with topiramate treatment.
This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory
effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has
been observed with the use of topiramate in placebo-controlled clinical trials
and in the post-marketing period. Generally, topiramate-induced metabolic
acidosis occurs early in treatment although cases can occur at any time during
treatment. Bicarbonate decrements are usually mild-moderate (average decrease
of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day
in pediatric patients); rarely, patients can experience severe decrements
to values below 10 mEq/L. Conditions or therapies that predispose to acidosis
(such as renal disease, severe respiratory disorders, status epilepticus,
diarrhea, surgery, ketogenic diet, or drugs) may be additive to the bicarbonate
lowering effects of topiramate.

In adults, the incidence
of persistent treatment-emergent decreases in serum bicarbonate (levels of <20
mEq/L at tw

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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use topiramate tablets safely and effectively. See full prescribing information for topiramate table...

These highlights do not include all the information needed to use topiramate tablets safely and effectively. See full prescribing information for topiramate tablets Topiramate Tablets, USP Rx Only Ini...

These highlights do not include all the information needed to use topiramate tablets safely and effectively. See full prescribing information for topiramate tablets Topiramate Tablets, USP Rx Only Ini...

These highlights do not include all the information needed to use topiramate tablets safely and effectively. See full prescribing information for topiramate tablets Topiramate Tablets, USP Rx Only Ini...

These highlights do not include all the information needed to use TOPAMAX safely and effectively. See full prescribing information for TOPAMAX TOPAMAX (topiramate) TABLETS for oral use TOPAMAX (topira...

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An infant developed a severe condition of recurrent and persistent watery diarrhea at 40 days of age. The child had been partially breast-fed, and the mother used topiramate for epilepsy. Hospital ex...

Topiramate has been widely utilized worldwide as an effective medication against partial- and generalized-onset seizures. Extended-release topiramate was developed to provide patients with the conveni...

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